An essential role for dendritic cells in human and experimental allergic rhinitis Alex KleinJan, PhD, a Monique Willart, BSc, a Leonie S. van Rijt, PhD, a Gert-Jan Braunstahl, MD, PhD, a Karolina Leman, BSc, a Steffen Jung, PhD, b Henk C. Hoogsteden, MD, PhD, a and Bart N. Lambrecht, MD, PhD a Rotterdam, The Netherlands, and Rehovot, Israel Background: In allergic rhinitis (AR) CD4 1 T H 2 lymphocytes control inflammation by secreting T H 2 cytokines, but little is known about how these cells are activated to cause disease. Objective: We sought to study the contribution of antigen- presenting dendritic cells (DCs) in activating T H 2 cells and controlling allergic inflammation. Methods: Nasal mucosal biopsy specimens were taken from patients with house dust mite allergy and perennial AR and healthy control subjects. DC numbers were evaluated by using immunohistochemistry. The functional role of DCs was studied in a novel mouse model for AR using BALB/c mice and CD11c– diphtheria toxin (DT) receptor transgenic mice. Results: In symptomatic patients with perennial AR, the number of CD1a 1 and CD11c 1 MHCII 1 DCs was higher in the epithelium and lamina propria of the nasal mucosa compared with that seen in healthy control subjects. In patients with AR, DCs had a more mature (CD86 1 ) phenotype and were found in close approximation with T lymphocytes. Similarly, in a mouse model of ovalbumin (OVA)-induced AR, CD11c 1 DCs accumulated in areas of nasal eosinophilic inflammation and clustered with CD4 1 T lymphocytes. CD11c 1 DCs were conditionally depleted during allergen challenge by means of systemic administration of DT to CD11c-diphtheria toxin receptor transgenic mice to address the functional role of DCs in maintaining inflammation. In the absence of CD11c 1 DCs, nasal OVA challenge in OVA-sensitized mice did not induce nasal eosinophilia and did not boost OVA-specific IgE levels or T H 2 cytokine production in the cervical lymph nodes. Conversely, when OVA-pulsed DCs were administered intranasally to sensitized mice, they strongly enhanced OVA- induced nasal eosinophilia and T H 2 cytokine production. Conclusions: These data in human subjects and mice suggest an essential role for nasal DCs in activation of effector T H 2 function leading to AR. Clinical implications: Nasal DCs play an essential role in AR and therefore constitute a novel target for therapeutic intervention. (J Allergy Clin Immunol 2006;118:1117-25.) Key words: Allergic rhinitis, antigen-presenting cell, dendritic cell, eosinophils, human, mouse, nasal mucosa, specific IgE Allergic rhinitis (AR) is one of the most common allergic diseases in Western society, affecting 5% to 22% of the general population. 1 AR often occurs simulta- neously with atopic asthma (AA), a condition now called united airways disease. 2 It is now clear that allergic in- flammation in AR and AA is controlled by effector CD4 T H 2 lymphocytes secreting IL-4, IL-5, IL-13, and GM- CSF in response to recognition of inhaled allergens. 3-7 It is less clear, however, how allergen-specific T H 2 cells are activated to cause disease on repeated allergen encoun- ter. CD4 lymphocyte activation requires the interaction of a specific T-cell receptor with peptide–MHC class II complexes on an antigen-presenting cell (APC) and requires the ligation of costimulatory receptors of the CD28 family on T cells by B7 family members of costimu- latory molecules (CD80 and CD86) on APCs. 8,9 It was re- cently shown that specialized antigen-presenting dendritic cells (DCs) provide both signals in the conducting air- ways. 10,11 In a mouse model of asthma, it was shown that myeloid DCs (mDCs) are attracted to the bronchial mucosa after inhaled allergen challenge in sensitized mice. 12 Along the same lines, allergen challenge with rel- evant allergen in human asthmatic subjects led to a recruit- ment of CD11c 1 mDCs in the airway mucosa and to a reduction in circulating blood DC precursors. 13,14 In view of the united airways concept, it is of interest to study whether DCs are similarly important in AR. Increased numbers of CD1a 1 Langerhans’ cells are found in the nasal mucosa of symptomatic patients with seasonal AR, and these numbers further increase after relevant nasal allergen challenge. 13,15-19 In symptomatic patients with AR, we previously described DCs bearing allergen- specific IgE in the nasal mucosa. 16,20 Treatment of patients with AR with intranasal corticosteroid therapy reduced dramatically the numbers of DCs in the nasal mucosa. 17,21 In this article we address the functional role of DCs in AR. First, we address whether DC numbers and matura- tion status are increased in nasal mucosal biopsy speci- mens in a large number of patients with perennial AR and in nasal tissues and draining lymph nodes (LNs) of allergen-challenged mice with AR. Second, we address From a the Department of Pulmonary Medicine, Erasmus MC, Rotterdam; and b the Weizman Institute, Rehovot. B. N. Lambrecht is supported by a Vidi grant of the Dutch Organization for Scientific Research and by an educational grant of AstraZeneca, The Netherlands. L. S. van Rijt is supported by an Erasmus University Fellowship Grant. Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest. Received for publication February 24, 2006; revised May 19, 2006; accepted for publication May 22, 2006. Available online August 29, 2006. Reprint requests: Bart N. Lambrecht, MD, PhD, Department of Pulmonary Medicine, Erasmus MC, Room Ee2257b, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. E-mail: b.lambrecht@erasmusmc.nl. 0091-6749/$32.00 Ó 2006 American Academy of Allergy, Asthma and Immunology doi:10.1016/j.jaci.2006.05.030 1117 Rhinitis, sinusitis, and ocular diseases